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. 2016 Feb;30(2):423-30.
doi: 10.1038/leu.2015.309. Epub 2015 Nov 3.

Clinical value of molecular subtyping multiple myeloma using gene expression profiling

N Weinhold  1 , C J Heuck  1 , A Rosenthal  2 , S Thanendrarajan  1 , C K Stein  1 , F Van Rhee  1 , M Zangari  1 , A Hoering  2 , E Tian  1 , F E Davies  1 , B Barlogie  1 , G J Morgan  1
Affiliations

Clinical value of molecular subtyping multiple myeloma using gene expression profiling

N Weinhold et al. Leukemia. 2016 Feb.

Abstract

Using a data set of 1217 patients with multiple myeloma enrolled in Total Therapies, we have examined the impact of novel therapies on molecular and risk subgroups and the clinical value of molecular classification. Bortezomib significantly improved the progression-free survival (PFS) and overall survival (OS) of the MMSET (MS) subgroup. Thalidomide and bortezomib positively impacted the PFS of low-risk (LoR) cases defined by the GEP70 signature, whereas high-risk (HiR) cases showed no significant changes in outcome. We show that molecular classification is important if response rates are to be used to predict outcomes. The t(11;14)-containing CD-1 and CD-2 subgroups showed clear differences in time to response and cumulative response rates but similar PFS and OS. Furthermore, complete remission was not significantly associated with the outcome of the MAF/MAFB (MF) subgroup or HiR cases. HiR cases were enriched in the MF, MS and proliferation subgroups, but the poor outcome of these groups was not linked to subgroup-specific characteristics such as MAF overexpression per se. It is especially important to define risk status if HiR cases are to be managed appropriately because of their aggressive clinical course, high rates of early relapse and the need to maintain therapeutic pressure on the clone.

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Conflict of interest statement

CONFLICT OF INTEREST

BB and CJH have received research funding from Celgene and Millennium. BB is a consultant to Celgene and Millennium, and is a co-inventor on patents and patent applications related to use of GEP in cancer medicine that have been licensed to Signal Genetics Inc. GJM has participated in advisory boards for, received payment for lectures and development of educational presentations from, and has received travel support from Celgene, Novartis, Merck, and Johnson & Johnson. FED has participated in advisory boards and spoken at meetings for Celgene, Ortho Biotech, and Novartis, and has received travel support to attend meetings from Celgene and Ortho Biotech. The remaining authors declare no conflict of interest.

Figures

Figure 1
Figure 1. Progression free survival before (TT2−) and after (TT2+/TT3a/TT3b) the introduction of novel drugs
The MS (A) and the HY (B) subgroup were selected as examples for subgroups with significantly improved PFS and the PR group (C) as an example for a subgroup that showed no improvement. The corresponding plots for OS are shown in D to F.
Figure 2
Figure 2. Impact of novel drugs on progression free survival
Forest plot for progression free survival comparisons between Total Therapies for each molecular subgroup.
Figure 3
Figure 3. Impact of novel drugs on time to complete remission
The figure shows a forest plot for comparison of time to complete remission between Total Therapies for each molecular subgroup.
Figure 4
Figure 4. Progression free survival in molecular subgroups according to risk status
Using the running log-rank test for the GEP70 score for PFS within the low-risk TT2 population and validating the result with TT3 data, we calculated a three-group risk predictor with an additional break point at 0.16. We split the data at the additional break point and at 0.66. We combined the subgroups with a favorable outcome (CD-1, CD-2, HY, and LB) and compared their PFS to MS (significantly improved by novel drugs) and the unfavorable subgroups MF and PR in low risk (A), medium risk (B) and high risk (C) cases.
Figure 5
Figure 5. Progression free survival from maintenance
Forest plot for comparison of progression free survival from maintenance between Total Therapies for GEP70 high and low risk cases.
Figure 6
Figure 6. Time to complete remission
The figure shows for the time to CR for CD-1, CD-2 and other molecular subgroups in TT2 and TT3 combined.
See this image and copyright information in PMC

References

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